DESCRIPTION: Viral-specific T lymphocytes play an important protective role in HIV infection. Although most infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, the targeted immune response fails to control HIV production. Freshly isolated peripheral blood lymphocytes from HIV-infected donors often lack HIV-specific cytotoxicity, which develops after overnight culture. To investigate reasons for in vivo T cell dysfunction, we analyzed by flow cytometry the relative expression of CD3 and CD3 , the signaling component of the T cell receptor complex. In 28 HIV-infected donors of all disease stages, a substantial fraction of circulating T cells downmodulate CD3 (fraction of CD3 -expressing T cells 0.74+0.16 vs 1.01+0.07 in normal donors, p<0.0000005). CD3 expression is downregulated more in CD8 than CD4 T cells, decreases early in infection and correlates with declining CD4 counts and disease stage. CD3 expression returns to normal over 6-10 hr of culture in an IL-2 dependent manner, coincident with restoration of viral-specific cytotoxicity. The hypothesis of this proposal is that abnormal CD3 expression by circulating T cells interferes with T cell antiviral functions of direct cytotoxicity and viral suppression by cytokine and chemokine secretion. Impaired T cell receptor signaling in vivo may help explain why the high frequency of HIV-specific precursor CTL fails to control HIV replication. This proposal will examine the extent to which CD3 downmodulation interferes with T cell signaling and cytokine production and determine whether certain subsets of T cells (such as activated, memory, cycling, apoptotic or HIV-specific CTL) are preferentially affected. Reasons for downmodulation will be investigated, including lack of specific helper function via IL-2 or other cytokine secretion, viral antigen excess causing CD8 T cell anergy, or inhibition by activated or HIV-infected macrophages or their products. Clinical trial and MACS cohort samples will be used to examine when CD3 downmodulation and T cell dysfunction occur and whether they improve with antiretroviral and immune based therapy.